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"Groth, M."
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Conserved Senescence Associated Genes and Pathways in Primary Human Fibroblasts Detected by RNA-Seq
Cellular senescence correlates with changes in the transcriptome. To obtain a complete view on senescence-associated transcription networks and pathways, we assessed by deep RNA sequencing the transcriptomes of five of the most commonly used laboratory strains of human fibroblasts during their transition into senescence. In a number of cases, we verified the RNA-seq data by real-time PCR. By determining cellular protein levels we observed that the age-related expression of most but not all genes is regulated at the transcriptional level. We found that 78% of the age-affected differentially expressed genes were commonly regulated in the same direction (either up- or down-regulated) in all five fibroblast strains, indicating a strong conservation of age-associated changes in the transcriptome. KEGG pathway analyses confirmed up-regulation of the senescence-associated secretory phenotype and down-regulation of DNA synthesis/repair and most cell cycle pathways common in all five cell strains. Newly identified senescence-induced pathways include up-regulation of endocytotic/phagocytic pathways and down-regulation of the mRNA metabolism and the mRNA splicing pathways. Our results provide an unprecedented comprehensive and deep view into the individual and common transcriptome and pathway changes during the transition into of senescence of five human fibroblast cell strains.
Journal Article
The anti-apoptotic Bcl-2 family protein A1/Bfl-1 regulates neutrophil survival and homeostasis and is controlled via PI3K and JAK/STAT signaling
Neutrophil granulocytes are innate effector cells of the first line of defense against pyogenic bacteria. Neutrophil lifespan is short, is prolonged by pro-inflammatory stimuli, controls functionality of the cells and can determine tissue damage. Experimental analysis of primary neutrophils is difficult because of their short lifespan and lack of possibilities of genetic manipulation. The Hoxb8 system of neutrophil differentiation from immortalized progenitor cells offers the advantage of unlimited production of neutrophils
in vitro
as well as easy genetic modification. We here use this system to analyze the role of the poorly characterized anti-apoptotic B-cell lymphoma protein 2 (Bcl-2) family member A1/Bfl-1 (Bcl-2-related protein A1) for survival and homeostasis of neutrophils and of neutrophil progenitors. Low constitutive mRNA and protein expression of A1 was detected, while A1 was transiently upregulated early during differentiation. Pro-inflammatory stimuli caused strong, mainly transcriptional, A1 upregulation, in contrast to posttranscriptional regulation of Mcl-1 (induced myeloid leukemia cell differentiation protein). Inhibitor studies showed that phosphoinositide-3 kinase (PI3K)/Akt and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) is required for A1 expression and survival of progenitors and mature neutrophils. ShRNA-mediated constitutive A1 knockdown (KD) impaired maintenance of progenitors. ShRNA experiments further showed that A1 was required early during neutrophil differentiation as well as in mature neutrophils upon pro-inflammatory stimulation. Our data further indicate differential regulation of the two anti-apoptotic proteins A1 and Mcl-1. Relevant findings were confirmed in primary human neutrophils. Our data indicate that A1, in addition to the well-established Mcl-1, substantially contributes to neutrophil survival and homeostasis. A1 may thus be a promising target for anti-inflammatory therapy.
Journal Article
The complete Peanuts : the definitive collection of Charles M. Schulz's comic strip masterpiece
The definitive collection of Charles M. Schulz's timeless masterpiece of comic art presenting, for the very first time, every strip from 1950 to 2000.
Book
Impact of the isotope effect on divertor detachment and pedestal structure in DIII-D
Dedicated H-mode hydrogen experiments has been conducted at DIII-D and are compared to a similar deuterium dataset under a range of divertor conditions, revealing significant effects of the isotope mass on divertor conditions and pedestal behavior. H-mode confinement is found to be systematically lower in hydrogen and experiences a more pronounced degradation with increased fueling. Hydrogen is found to have a higher ne,sep at similar fueling rates. When comparing hydrogen and deuterium discharges under similar divertor regimes, the hydrogen cases are shown to have a higher electron density and lower electron temperature in the outer divertor. Hydrogen and deuterium density ramps demonstrate a 20% higher ion current and of a 17% higher upstream density at detachment onset in hydrogen. The trends of divertor conditions with isotope mass through detachment are studied through a 2 point model analysis and detailed 2D interpretive SOLPS-ITER modeling. Both approaches are able to reproduce key experimental trends. Highlighted in the modeling are a significant role of the ion sound speed, the momentum balance, and carbon sputtering and radiation. An analysis of the particle source in the 2D modeling confirms a higher core particle source for hydrogen, consistent with the experimental hydrogen pedestal structure. However, deuterium is shown to have a lower ionization mean free path at the target than in hydrogen at the same upstream density, contrary to expected scaling with isotope mass. An experimental analysis of the pedestal stability and neutral fueling demonstrates that neither of these effects are sufficient to explain the pedestal differences between isotopes nor the hydrogen pedestal structure respectively. These results indicate that increasing ion mass is likely beneficial for divertor performance in future devices, reducing heat and particle fluxes as well as the ne,sep required for detachment.
Journal Article
Validation of the ERO2.0 code using W7-X and JET experiments and predictions for ITER operation
The paper provides an overview of recent modelling of global material erosion and deposition in the fusion devices Wendelstein 7-X (W7-X), JET and ITER using the Monte-Carlo code ERO2.0. For validating the modelling tool in a three-dimensional environment, W7-X simulations are performed to describe carbon erosion from the graphite test divertor units, which were equipped in operational phase OP 1.2 and analysed post-mortem. Synthetic spectroscopy of carbon line emission is compared with experimental results from the divertor spectrometer measurement system, showing a good agreement in the e-folding lengths in the radial intensity profiles of carbon. In the case of metallic wall materials, earlier modelling of the Be/W environment in JET and ITER is revisited and extended with an updated set of sputtering and reflection data, as well as including the mixing model for describing the Be/W dynamics in the divertor. Motivated by recent H/D/T isotope experiments in JET, limited and diverted configuration pulses are modelled, showing the expected trend of both Be and W erosion increasing with isotope mass. For the JET diverted configuration pulses, it is shown that Be migrates predominantly to the upper part of the inner divertor where it initially leads to strong W erosion. With longer exposure time, the growth of a Be deposited layer leads to a reduction of W erosion in that region. A similar trend is observed in simulations of the ITER baseline Q = 10 scenario, however with a more symmetric Be migration pattern leading to deposition also on the outer divertor.
Journal Article
Analysis of pooled genome sequences from Djallonke and Sahelian sheep of Ghana reveals co-localisation of regions of reduced heterozygosity with candidate genes for disease resistance and adaptation to a tropical environment
Background
The Djallonke sheep is well adapted to harsh environmental conditions, and is relatively resistant to Haemonchosis and resilient to animal trypanosomiasis. The larger Sahelian sheep, which cohabit the same region, is less well adapted to these disease challenges. Haemonchosis and Trypanosomiasis collectively cost the worldwide animal industry billions of dollars in production losses annually.
Results
Here, we separately sequenced and then pooled according to breed the genomes from five unrelated individuals from each of the Djallonke and Sahelian sheep breeds (sourced from Ghana), at greater than 22-fold combined coverage for each breed. A total of approximately 404 million (97%) and 343 million (97%) sequence reads from the Djallonke and Sahelian breeds respectively, were successfully mapped to the sheep reference genome Oar v3.1. We identified approximately 11.1 million and 10.9 million single nucleotide polymorphisms (SNPs) in the Djallonke and Sahelian breeds, with approximately 15 and 16% respectively of these not previously reported in sheep. Multiple regions of reduced heterozygosity were also found; 70 co-localised within genomic regions harbouring genes that mediate disease resistance, immune response and adaptation in sheep or cattle. Thirty- three of the regions of reduced heterozygosity co-localised with previously reported genes for resistance to haemonchosis and trypanosomiasis.
Conclusions
Our analyses suggest that these regions of reduced heterozygosity may be signatures of selection for these economically important diseases.
Journal Article
Identifying dietary patterns and associated health-related lifestyle factors in the adult Danish population
Background/objectives:
To identify and describe dietary patterns in Danish adults and to examine which demographic and health-related lifestyle factors are associated with dietary patterns.
Subjects/methods:
Data derived from the Danish national survey of diet and physical activity collected in 2003–2008 and included 1569 men and 1785 women. Diet was assessed by a 7-day pre-coded food diary. Information on age, gender, weight, height, physical activity, smoking habits, educational level and attitudes towards healthy eating habits was derived from face-to-face interviews. Principal component analysis was applied to explore dietary patterns. Associations with lifestyle factors were examined by means of multiple regression analyses.
Results:
Three major dietary patterns were identified: a ‘traditional’ pattern correlated with intake of rye bread, white bread, fat on bread, cheese, jam, cold meat, minced meat, potatoes and gravy, and cake and biscuits; a ‘health-conscious’ pattern correlated with coarse bread, fruit, vegetables, low-fat dairy, nuts, water and tea; and a ‘fast food’ pattern correlated with pizza, hamburger/spring rolls, crisps, rice and pasta, sugar-sweetened soft drinks and sweets. The ‘traditional’ pattern was positively associated with male gender and age, whereas the ‘health-conscious’ pattern was positively associated with being female, increasing age and educational level. The ‘fast food’ pattern was inversely associated with age and smoking.
Conclusions:
Three distinct dietary patterns were identified, and associated lifestyle and demographic factors were characterised. The findings are valuable in targeting future nutrition education and will enable more focused strategies in communicating food-based dietary guidelines.
Journal Article
Multi-staged ERO2.0 simulation of material erosion and deposition in recessed mirror assemblies in JET and ITER
The deposition/erosion on optical diagnostic components—mirrors—is a critical issue in reactor class devices with long-pulsed high fluence plasma operation. The paper presents results of the three-dimensional Monte–Carlo code ERO2.0 for two diagnostic aperture and first mirror geometries to be deployed in ITER, along with a separate simulation study that aims to replicate results from an experimental first-mirror study carried out on JET. Promisingly, very little plasma and impurity deposition on mirrors for the anticipated plasma durations is found in the ERO2.0 modelling taking into account the current ITER Research Plan and a material mix with beryllium first wall and a tungsten divertor. The post-mortem analysis of mirrors exposed during the experiment and the initial benchmarking efforts on the JET mirror experiment are also broadly consistent, increasing the confidence in predictions for ITER.
Journal Article